2-165354531-G-C

Position:

• chr2-165354531-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001040142.2(SCN2A):​c.3259G>C​(p.Val1087Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,808 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V1087M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: SCN2A NM_001040142.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.63

Genes affected

SCN2A (HGNC:10588): (sodium voltage-gated channel alpha subunit 2) Voltage-gated sodium channels are transmembrane glycoprotein complexes composed of a large alpha subunit with four repeat domains, each of which is composed of six membrane-spanning segments, and one or more regulatory beta subunits. Voltage-gated sodium channels function in the generation and propagation of action potentials in neurons and muscle. This gene encodes one member of the sodium channel alpha subunit gene family. Allelic variants of this gene are associated with seizure disorders and autism spectrum disorder. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Nov 2016]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SCN2A. . Trascript score misZ 8.7114 (greater than threshold 3.09). GenCC has associacion of gene with seizures, benign familial infantile, 3, Dravet syndrome, benign familial neonatal-infantile seizures, malignant migrating partial seizures of infancy, complex neurodevelopmental disorder, developmental and epileptic encephalopathy, 11, developmental and epileptic encephalopathy, West syndrome, benign familial infantile epilepsy, episodic ataxia, type 9.
• BP4: Computational evidence support a benign effect (MetaRNN=0.18149295).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SCN2A	NM_001040142.2	c.3259G>C	p.Val1087Leu	missense_variant	17/27	ENST00000375437.7
SCN2A	NM_001371246.1	c.3259G>C	p.Val1087Leu	missense_variant	17/27	ENST00000631182.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SCN2A	ENST00000375437.7	c.3259G>C	p.Val1087Leu	missense_variant	17/27	5	NM_001040142.2	P1
SCN2A	ENST00000631182.3	c.3259G>C	p.Val1087Leu	missense_variant	17/27	5	NM_001371246.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461808 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727200

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.38	T;.;T;.;T;T;.
Eigen	Benign	-0.16
Eigen_PC	Benign	0.037
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.83	T;.;T;.;.;.;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.18	T;T;T;T;T;T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	0.42	N;N;.;N;N;N;N
MutationTaster	Benign	0.72	D;D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.71	N;.;.;.;.;N;N
REVEL	Benign	0.15
Sift	Uncertain	0.028	D;.;.;.;.;D;D
Sift4G	Benign	0.72	T;.;.;T;.;T;T
Polyphen		0.0030	B;B;.;B;B;B;B
Vest4		0.23
MutPred		0.43		Loss of ubiquitination at K1084 (P = 0.0837);Loss of ubiquitination at K1084 (P = 0.0837);.;Loss of ubiquitination at K1084 (P = 0.0837);Loss of ubiquitination at K1084 (P = 0.0837);Loss of ubiquitination at K1084 (P = 0.0837);Loss of ubiquitination at K1084 (P = 0.0837);
MVP		0.78
ClinPred		0.33	T
GERP RS		4.3
Varity_R		0.14
gMVP		0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs765278777; hg19: chr2-166211041;